Methods and pharmaceutical preparations for elevating ketone utilization

ABSTRACT

The invention relates generally to the field of medical treatment. More particularly, the invention relates to treating a patient in order to increase the amount of ketones metabolized by mitochondria. Exemplary patients include those with Alzheimer&#39;s disease and insulin resistance.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application63/033,583, filed Jun. 2, 2020, which is incorporated herein byreference.

FIELD OF THE INVENTION

The invention relates generally to the field of medical treatment. Moreparticularly, the invention relates to treating a patient in order toincrease the amount of ketones metabolized by mitochondria. Exemplarypatients include those with Alzheimer's disease and insulin resistance.

BACKGROUND OF THE INVENTION

Separately, ketone bodies are water-soluble ketone molecules that areproduced by the liver from fatty acids. Ketone bodies can be produced atvarious points in time, such as fasting, starvation, and prolongedexercise. Ketone bodies can also be metabolized by mitochondria in cellsin order to provide energy for the cell. Under typical biologicalconditions, however, mitochondria metabolize glucose in order to provideenergy to the cell. For a given amount of energy production, ketonemetabolism of BHB (a major ketone) consumes less oxygen than glucosemetabolism.

Ketone metabolism is an important biochemical process in the body. Assuch, if a particular cell is unable to metabolize ketones properly,which can happen for a variety of reasons, the cell might suffer,including cell death.

(−)-Hydroxycitric acid, its salts, and its derivatives (collectively:“HCA”) are known to have various biological properties. For example, ithas been shown that HCA is a competitive inhibitor of ATP citrate lyase,which converts citrate into oxaloacetate and acetyl CoA. One isomer ofHCA, (2S,3R)-HCA, inhibits pancreatic alpha-amylase and intestinalalpha-glucosidase, which causes a reduction in carbohydrate metabolismin vitro. HCA has been administered to patients for various medicalreasons in the United States in dosages ranging up to approximately 12grams per day (providing roughly 6-7 grams of HCA).

SUMMARY

The inventors have made the surprising discovery that administering HCAcauses an increase in oxygen saturation and blood hemoglobin levels inindividuals. This action by HCA has not heretofore been recognized eventhough salts of (−)-hydroxycitric acid have been commercially availablefor many years and have been administered dosages ranging up toapproximately 12 g/day (providing roughly 6-7 g/day of (−)-hydroxycitricacid).

Provided is a method of treating a subject, including administering tothe subject a therapeutically effective amount of a formulationincluding HCA, wherein a medical professional has hypothesized ordetermined that the subject is underutilizing ketones, therebyincreasing ketone utilization.

Provided is a kit including HCA and instructions directing a subject toingest the HCA if the subject desires increased athletic performance.

These and other objects, advantages, and features of the invention willbecome apparent to those persons skilled in the art upon reading thedetails of the invention as more fully described below.

Objects and Advantages

It is an objective of the present invention to provide a method forrapidly enhancing blood hemoglobin and blood oxygen saturation levels,for example as shown via fNIRS measurements of the brain, in anindividual with suboptimal levels.

These objects and advantages are not derived from the actions commonlyclaimed for the use of HCA but rather rely upon mechanisms notheretofore uncovered and that yield measurable increases in bloodhemoglobin and oxygen saturation levels in as little as 10-15 minutes ofingestion of an appropriate formulation on an empty stomach.

These and other objects, advantages, and features of the invention willbecome apparent to those persons skilled in the art upon reading thedetails of the method and formulation as more fully described below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a fNIRS (functional Near Infrared Spectroscopy) measurementof Subject 1, middle-aged male who consumed one “Bolus Dose Shot”containing 2.5 grams of potassium-magnesium HCA salt. Testing wasperformed via fNIRS. The section before the first vertical line is thereference or baseline period. This line also marks the dosing point. Thesection after the second vertical line indicates a rather dramaticchange in blood hemoglobin and oxygen levels that began 12-15 minutesfollowing dosing. The top, thickest line is HbT=total hemoglobinconcentration, the middle line is HbO or HbO2 (oxygen saturation), andthe bottom thinnest line is deoxygen saturation.

FIG. 2 shows a fNIRS measurement of Subject 2, male in late 50s whofirst consumed one “Bolus Dose Shot” containing 2.5 grams ofpotassium-magnesium HCA salt followed by a second “Bolus Dose Shot”thirty minutes after the first. The lines are, from thickest tothinnest, are Hbt, HbO, deoxygen saturation.

FIG. 3 shows a fNIRS of Subject 3, male, approximately 50 years old, whofirst consumed one “Bolus Dose Shot” containing 2.5 grams ofpotassium-magnesium HCA salt followed by a second “Bolus Dose Shot”thirty minutes after the first. The lines are, from thickest tothinnest, are Hbt, HbO, deoxygen saturation.

FIG. 4 shows a fNIRS of Subject 4, female of approximately thirty yearsof age who consumed one “Bolus Dose Shot” containing 2.5 grams ofpotassium-magnesium HCA salt with testing via fNIRS. The lines are, fromthickest to thinnest, are Hbt, HbO, deoxygen saturation.

FIG. 5 shows a hypothesized mechanism for the biochemical effects of HCAadministration.

DETAILED DESCRIPTION

Provided is a method of treating a subject, including administering tothe subject a therapeutically effective amount of a formulationincluding HCA, wherein a medical professional has hypothesized ordetermined that the subject is underutilizing ketones, therebyincreasing ketone utilization.

Provided is a kit including HCA and instructions directing a subject toingest the HCA if the subject desires increased athletic performance.

Before the present invention is described, it is to be understood thatthis invention is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, some potential andpreferred methods and materials are now described. All publicationsmentioned herein are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. It is understood that the present disclosuresupersedes any disclosure of an incorporated publication to the extentthere is a contradiction.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Definitions

HCA includes (−)-hydroxycitric acid, salts thereof, and derivativesthereof. (−)-Hydroxycitric acid itself can be referred as such, or asthe free acid of HCA. (−)-Hydroxycitric acid has the CAS number6205-14-7, the preferred IUPAC name of1,2-dihydroxypropane-1,2,3-tricarboxylic acid, and the chemicalstructure shown below. In some cases, the salt of (−)-hydroxycitric acidis recognized as a pharmaceutically acceptable salt thereof.

Blood oxygen saturation is the amount of oxygen-saturated hemoglobin inblood divided by the total amount of hemoglobin in the blood (i.e.saturated plus unsaturated).

Blood oxygen saturation, blood oxygenation level, and oxygen saturationare used interchangeably herein.

The terms “patient” and “subject” are used interchangeably herein.

Preferred Embodiments

The free acid form and various salts of (−)-hydroxycitric acid (calcium,magnesium, potassium, sodium, etc. and mixtures thereof) have beenavailable commercially for many years. Any of these materials can beused to fulfill the invention revealed here, but with varying degrees ofsuccess. Exact dosing will depend upon the form of HCA used, the weightof the individual involved, metabolism, and the other components of thediet, etc. Due to the advantages of maximizing the uptake andutilization of the HCA salt, enhanced delivery formulations such as U.S.Pat. No. 10,376,483 “Bolus Dose” and U.S. Pat. No. 10,561,630 “CapsuleLiquid Delivery” can be used.

Ketone Utilization

Ketone bodies are water-soluble ketone molecules that are produced bythe liver from fatty acids. Ketone bodies can be produced at variouspoints in time, such as fasting, starvation, and prolonged exercise.Ketone bodies can also be metabolized by mitochondria in cells in orderto provide energy for the cell. Under typical biological conditions,however, mitochondria metabolize glucose in order to provide energy tothe cell. For a given amount of energy production, ketone metabolism ofBHB (a major ketone) consumes less oxygen than glucose metabolism.

Ketone metabolism is an important biochemical process in the body. Assuch, if a particular cell is unable to metabolize ketones properly,which can happen for a variety of reasons, the cell might suffer,including cell death.

Administration of HCA can be used to increase ketone utilization.Provided is a method of treating a subject, including: (i) administeringto the subject a therapeutically effective amount of a formulationincluding HCA, wherein a medical professional has hypothesized ordetermined that the subject is underutilizing ketones, therebyincreasing ketone utilization.

Thus, the method can be useful in treating subjects with unhealthily lowketone utilization. Due to variations between individuals, what isunhealthy depends upon numerous factors, and as such no single numericalvalue necessarily separates a healthy ketone utilization level from anunhealthy ketone utilization level. In some cases, prior to theadministration, a medical professional determined or hypothesized thatthe ketone utilization of the patient is unhealthily low. The medicalprofession can be, for example, a doctor, nurse, or paramedic.

Some neurological diseases are hypothesized to be caused or worsened byunder utilization of ketones. In some cases, the subject has beendiagnosed by a medical professional with one or more conditions selectedfrom the group consisting of: dementia, insulin resistance, reactivehyperglycemia, diabetes, elevated blood sugar levels, mental stress, andphysical stress.

The amount of HCA necessary to achieve an increase in ketone utilizationcan vary depending on the individual's body mass, sex, age, healthconditions, and other factors. In some cases, the administered HCA is(−)-hydroxycitric acid. In other cases, the administered HCA is a saltor derivative of (−)-hydroxycitric acid.

In some cases, the administered HCA corresponds to 500 mg to 10,000 mgof (−)-hydroxycitric acid, e.g. 1,500 mg to 5,000 mg. For example, ifthe HCA is (−)-hydroxycitric acid itself, then 500 mg to 10,000 mg of(−)-hydroxycitric acid is administered. However, suppose that theadministered HCA is the tri-sodium salt of (−)-hydroxycitric acid. Insuch a case, since the tri-sodium salt has a molecular weight of 274g/mol and (−)-hydroxycitric acid is 208 g/mol, then administering 5,000mg of the tri-sodium salt would correspond to (5,000 divided by 274multiplied by 208) or 3,796 mg of (−)-hydroxycitric acid.

As described above, the HCA can be (−)-hydroxycitric acid, a saltthereof, or a derivative thereof. Suitable salts include sodium,potassium, calcium, magnesium, and potassium-magnesium. Suitablederivates include a lactone, an amide, and an ester. As such, in somecases, the HCA is selected from the group consisting of(−)-hydroxycitric acid, a lactone of (−)-hydroxycitric acid, a sodiumsalt of (−)-hydroxycitric acid, a potassium salt of (−)-hydroxycitricacid, a calcium salt of (−)-hydroxycitric acid, a magnesium salt of(−)-hydroxycitric acid, a potassium-magnesium salt of (−)-hydroxycitricacid, an amide derivative of (−)-hydroxycitric acid, and an esterderivative of (−)-hydroxycitric acid.

In some case, the HCA is a potassium-magnesium salt of (−)-hydroxycitricacid.

The HCA can be administered in any suitable fashion. For instance, theHCA can be administered orally, e.g. as a solid, as an aqueous solution,in a capsule, or in a pill. Alternatively, the HCA can be administeredintravenously or via gastric intubation.

In some cases, the method further includes administering triglyceridesor coconut oil. In some cases, the method further includes administeringa supplement promoting hepatic ketogenesis, e.g. carnitine oralpha-glyceryl phosphoryl choline.

Kit Relating to Athletic Performance

Provided is a kit including HCA and instructions directing a subject toingest the HCA if the subject desires increased athletic performance.

If appropriate, each of the aspects discussed above regarding the methodof increasing ketone utilization.

In some cases, the athletic performance is aerobic endurance. In somecases, the athletic performance is quicker recovery after exercise.

In some cases, the instructions direct the subject to ingest HCAcorresponding to 500 mg to 10,000 mg of (−)-hydroxycitric acid, such as1,500 mg to 5,000 mg. HCA can be selected from the group consisting of(−)-hydroxycitric acid, a lactone of (−)-hydroxycitric acid, a sodiumsalt of (−)-hydroxycitric acid, a potassium salt of (−)-hydroxycitricacid, a calcium salt of (−)-hydroxycitric acid, a magnesium salt of(−)-hydroxycitric acid, a potassium-magnesium salt of (−)-hydroxycitricacid, an amide derivative of (−)-hydroxycitric acid, and an esterderivative of (−)-hydroxycitric acid. Sometimes the HCA is apotassium-magnesium salt of (−)-hydroxycitric acid.

Also provided is method including packaging a formulation includingpackaging into a container HCA and instructions directing a subject toingest the HCA if the subject desires increased athletic performance.This method corresponds to the kit described in this section, and caninclude each of the aspects described above relating to the kit.

In some cases, the kit further includes triglycerides or coconut oil. Insome cases, the kit further includes administering a supplementpromoting hepatic ketogenesis, e.g. carnitine or alpha-glycerylphosphoryl choline.

Method of Increasing Blood Oxygen Saturation

Provided is a method of treating a subject, including: (i) determiningan initial level of blood oxygen saturation in the subject, and (ii)administering to the subject a therapeutically effective amount of aformulation including HCA, thereby increasing blood oxygen saturation.

The amount of HCA necessary to achieve an increase in blood oxygensaturation can vary depending on the individual's body mass, sex, age,health conditions, and other factors. In some cases, the administeredHCA is (−)-hydroxycitric acid. In other cases, the administered HCA is asalt or derivative of (−)-hydroxycitric acid.

In some cases, the administered HCA corresponds to 500 mg to 10,000 mgof (−)-hydroxycitric acid, e.g. 1,500 mg to 5,000 mg. For example, ifthe HCA is (−)-hydroxycitric acid itself, then 500 mg to 10,000 mg of(−)-hydroxycitric acid is administered. However, suppose that theadministered HCA is the tri-sodium salt of (−)-hydroxycitric acid. Insuch a case, since the tri-sodium salt has a molecular weight of 274g/mol and (−)-hydroxycitric acid is 208 g/mol, then administering 5,000mg of the tri-sodium salt would correspond to (5,000 divided by 274multiplied by 208) or 3,796 mg of (−)-hydroxycitric acid.

In some cases, the method further comprises determining an adjustedlevel of blood oxygen saturation in the subject. Thus, a firstdetermining is performed, and then the administration is performed, andthen the second determining of the adjusted level is performed. Anysuitable length of time can elapse between each of these steps. Forinstance, 30 minutes to 300 minutes can elapse between the firstdetermining and the administration. For instance, 10 minutes to 600minutes can elapse between the administration and the seconddetermining, which is of the adjusted level. The first and subsequentadministrations typically, but not necessarily, involve administeringthe same HCA formulation.

In some cases, the method further comprises performing a secondadministration of a formulation comprising HCA in an amount based on thedifference between the initial level and the adjusted level. Forexample, if blood oxygen saturation did not measurably change, then alarger amount of HCA can be administered. However, if blood oxygensaturation increased to 100% or nearly 100%, then the secondadministration can be of a smaller maintenance dose to keep oxygensaturation at or near 100%. This cycle of determining the level ofoxygen saturation and administering HCA can be repeated any suitablenumber of times, with any suitable length of time elapsing between eachstep. A medical professional can use their professional judgement todetermine such factors.

As described above, the HCA can be (−)-hydroxycitric acid, a saltthereof, or a derivative thereof. Suitable salts include sodium,potassium, calcium, magnesium, and potassium-magnesium. Suitablederivates include a lactone, an amide, and an ester. As such, in somecases, the HCA is selected from the group consisting of(−)-hydroxycitric acid, a lactone of (−)-hydroxycitric acid, a sodiumsalt of (−)-hydroxycitric acid, a potassium salt of (−)-hydroxycitricacid, a calcium salt of (−)-hydroxycitric acid, a magnesium salt of(−)-hydroxycitric acid, a potassium-magnesium salt of (−)-hydroxycitricacid, an amide derivative of (−)-hydroxycitric acid, and an esterderivative of (−)-hydroxycitric acid.

In some case, the HCA is a potassium-magnesium salt of (−)-hydroxycitricacid.

As described above, this method can be used to increase blood oxygensaturation. As such, it is useful for treating subjects with unhealthilylow blood oxygen saturation. Due to variations between individuals, whatis unhealthy depends upon numerous factors, and as such no singlenumerical value necessarily separates a healthy blood oxygen saturationlevel from an unhealthy blood oxygen saturation level. In some cases,prior to the administration, a medical professional determined that theblood oxygen saturation of the patient is unhealthily low. The medicalprofession can be, for example, a doctor, nurse, or paramedic.

Blood oxygen saturation can be measured in various ways, such asarterial oxygen saturation (SaO₂), venous oxygen saturation (SvO₂),peripheral oxygen saturation (SpO₂), and tissue oxygen saturation(StO₂). In some cases, the initial SaO₂ is determined to be 90% or less.In some cases, the initial SvO₂ is determined to be 60% or less. In somecases a pulse oximeter is used to measure blood oxygen saturation.Although pulse oximeters normally directly measure SpO₂, many areconfigured to give an output that correlates with SaO₂. Thus, in somecases, the pulse oximeter measures a SpO₂ that correlates with an SaO₂of 90% or less, or the pulse oximeter determines SaO₂ to be 90% or less.In other cases, the determining is using infrared spectroscopy. In somecases, the determining involves obtaining a blood sample from thepatient. In some cases, the determining involves performing anarterial-blood gas test (ABG).

In some cases, the subject has been diagnosed by a medical professionalwith one or more conditions selected from the group consisting of:dementia, insulin resistance, reactive hyperglycemia, diabetes, elevatedblood sugar levels, mental stress, and physical stress.

The HCA can be administered in any suitable fashion. For instance, theHCA can be administered orally, e.g. as a solid, as an aqueous solution,in a capsule, or in a pill. Alternatively, the HCA can be administeredintravenously.

In some cases, the amount of HCA administered is sufficient to increaseblood oxygen saturation levels by 5% or more within 1 hour ofadministration, e.g. by 10% or more, or 25% or more.

In some cases, the administration results in an increase in oxygensaturation such that the subject no longer has unhealthily low oxygensaturation.

In some cases, the method further includes administering triglyceridesor coconut oil. In some cases, the method further includes administeringa supplement promoting hepatic ketogenesis, e.g. carnitine oralpha-glyceryl phosphoryl choline.

Kit Relating to Blood Oxygen Saturation

Provided is a kit including HCA and instructions directing a subject toingest the HCA if the subject is determined to have unhealthily lowblood oxygen saturation.

If appropriate, each of the aspects discussed above regarding the methodof increasing blood oxygen saturation can also be applied to the kitdescribed in this section.

As described above, due to variations between individuals, what isunhealthy depends upon numerous factors, and as such no single numericalvalue necessarily separates a healthy blood oxygen saturation level froman unhealthy blood oxygen saturation level. However, in some cases, thesubject was determined to have an arterial oxygen saturation level(SaO₂) of 90% or less. In other cases, a medical professional determinedthat the subject has an unhealthily low blood oxygen saturation. In somecases, the instructions describe an arterial oxygen saturation level(SaO₂) of 89.9% as unhealthily low.

The instructions can be provided in any suitable manner, e.g. as a labelattached to a container holding the HCA, or on a piece of paper includedin a packaging along with a container holding the HCA. The HCA can be asolid, in an aqueous solution, in a capsule, or in a pill. In somecases, the HCA is in the form of an aqueous solution.

In some cases, the kit further includes a pulse oximeter, andinstructions direct the subject to determine the subject's arterialoxygen saturation level (SaO₂) with the pulse oximeter.

In some cases, the instructions direct the subject to ingest HCAcorresponds to 500 mg to 10,000 mg of (−)-hydroxycitric acid, e.g. 1,500mg to 5,000 mg. In some cases, the HCA is selected from the groupconsisting of (−)-hydroxycitric acid, a lactone of (−)-hydroxycitricacid, a sodium salt of (−)-hydroxycitric acid, a potassium salt of(−)-hydroxycitric acid, a calcium salt of (−)-hydroxycitric acid, amagnesium salt of (−)-hydroxycitric acid, a potassium-magnesium salt of(−)-hydroxycitric acid, an amide derivative of (−)-hydroxycitric acid,and an ester derivative of (−)-hydroxycitric acid. In some cases, theHCA is a potassium-magnesium salt of (−)-hydroxycitric acid.

Also provided is method including packaging a formulation includingpackaging into a container HCA and instructions directing a subject toingest the HCA if the subject is determined to have unhealthily lowblood oxygen saturation. This method corresponds to the kit described inthis section, and can include each of the aspects described aboverelating to the kit.

In some cases, the kit further includes triglycerides or coconut oil. Insome cases, the kit further includes administering a supplementpromoting hepatic ketogenesis, e.g. carnitine or alpha-glycerylphosphoryl choline.

Method of Increasing Blood Hemoglobin

Provided is a method of treating a subject, including: (i) determiningan initial level of blood hemoglobin in the subject, and (ii)administering to the subject a therapeutically effective amount of aformulation including HCA, thereby increasing blood hemoglobin.

As appropriate, each of the aspects discussed above regarding the methodof increasing blood oxygen saturation can also be applied to the methodsdescribed in this section, provided that such steps are adapted to bloodhemoglobin levels instead of blood oxygen saturation levels.

The amount of HCA necessary to achieve an increase in blood hemoglobincan vary depending on the individual's body mass, sex, age, healthconditions, and other factors. In some cases, the administered HCA is(−)-hydroxycitric acid. In other cases, the administered HCA is a saltor derivative of (−)-hydroxycitric acid.

In some cases, the administered HCA corresponds to 500 mg to 10,000 mgof (−)-hydroxycitric acid, e.g. 1,500 mg to 5,000 mg. For example, ifthe HCA is (−)-hydroxycitric acid itself, then 500 mg to 10,000 mg of(−)-hydroxycitric acid is administered. However, suppose that theadministered HCA is the tri-sodium salt of (−)-hydroxycitric acid. Insuch a case, since the tri-sodium salt has a molecular weight of 274g/mol and (−)-hydroxycitric acid is 208 g/mol, then administering 5,000mg of the tri-sodium salt would correspond to (5,000 divided by 274multiplied by 208) or 3,796 mg of (−)-hydroxycitric acid.

In some cases, the method further comprises determining an adjustedlevel of blood hemoglobin in the subject. Thus, a first determining isperformed, and then the administration is performed, and then the seconddetermining of the adjusted level is performed. Any suitable length oftime can elapse between each of these steps. For instance, 30 minutes to300 minutes can elapse between the first determining and theadministration. For instance, 10 minutes to 600 minutes can elapsebetween the administration and the second determining, which is of theadjusted level.

In some cases, the method further comprises performing a secondadministration of a formulation comprising HCA in an amount based on thedifference between the initial level and the adjusted level. The firstand subsequent administrations typically, but not necessarily, involveadministering the same HCA formulation. For example, if blood hemoglobindid not measurably change, then a larger amount of HCA can beadministered. However, if blood hemoglobin increased by 25% or more,then the second administration can be smaller. This cycle of determiningthe level of blood hemoglobin and administering HCA can be repeated anysuitable number of times, with any suitable length of time elapsingbetween each step. A medical professional can use their professionaljudgement to determine such factors.

As described above, the HCA can be (−)-hydroxycitric acid, a saltthereof, or a derivative thereof. Suitable salts include sodium,potassium, calcium, magnesium, and potassium-magnesium. Suitablederivates include a lactone, an amide, and an ester. As such, in somecases, the HCA is selected from the group consisting of(−)-hydroxycitric acid, a lactone of (−)-hydroxycitric acid, a sodiumsalt of (−)-hydroxycitric acid, a potassium salt of (−)-hydroxycitricacid, a calcium salt of (−)-hydroxycitric acid, a magnesium salt of(−)-hydroxycitric acid, a potassium-magnesium salt of (−)-hydroxycitricacid, an amide derivative of (−)-hydroxycitric acid, and an esterderivative of (−)-hydroxycitric acid.

In some case, the HCA is a potassium-magnesium salt of (−)-hydroxycitricacid.

As described above, this method can be used to increase bloodhemoglobin. As such, it is useful for treating subjects with unhealthilylow blood hemoglobin. Due to variations between individuals, what isunhealthy depends upon numerous factors, and as such no single numericalvalue necessarily separates a healthy blood hemoglobin level from anunhealthy blood hemoglobin level. In some cases, prior to theadministration, a medical professional determined that the bloodhemoglobin of the patient is unhealthily low. The medical profession canbe, for example, a doctor, nurse, or paramedic.

Blood oxygen saturation can be measured in any suitable manner. In somecases, the level of blood hemoglobin is less than 130 g/L for a male orless than 120 g/L for a female. In some cases, the initial level ofblood hemoglobin is 100 g/L or less.

In some cases, the subject has been diagnosed by a medical professionalwith one or more conditions selected from the group consisting of:dementia, insulin resistance, reactive hyperglycemia, diabetes, elevatedblood sugar levels, mental stress, and physical stress.

The HCA can be administered in any suitable fashion. For instance, theHCA can be administered orally, e.g. as a solid, as an aqueous solution,in a capsule, or in a pill. Alternatively, the HCA can be administeredintravenously.

In some cases, the amount of HCA administered is sufficient to increaseblood hemoglobin by 5% or more within 1 hour of administration, e.g. by10% or more, or 25% or more.

In some cases, the administration results in an increase in bloodhemoglobin such that the subject no longer has low blood hemoglobin.

In some cases, the method further includes administering triglyceridesor coconut oil. In some cases, the method further includes administeringa supplement promoting hepatic ketogenesis, e.g. carnitine oralpha-glyceryl phosphoryl choline.

Triglyceride and Cortisol Levels

Provided is a method of treating a subject, including: (i) determiningan initial level of triglycerides or cortisol in the subject, and (ii)administering to the subject a therapeutically effective amount of aformulation including HCA, thereby reducing triglycerides, cortisol, orboth.

In some cases, the therapeutically effective amount of the formulationcomprising HCA is sufficient to produce a 10% decrease in the level oftriglycerides or cortisol within 6 hours.

The amount of HCA necessary to achieve an increase in blood oxygensaturation can vary depending on the individual's body mass, sex, age,health conditions, and other factors. In some cases, the administeredHCA is (−)-hydroxycitric acid. In other cases, the administered HCA is asalt or derivative of (−)-hydroxycitric acid.

In some cases, the administered HCA corresponds to 500 mg to 10,000 mgof (−)-hydroxycitric acid, e.g. 1,500 mg to 5,000 mg. For example, ifthe HCA is (−)-hydroxycitric acid itself, then 500 mg to 10,000 mg of(−)-hydroxycitric acid is administered. However, suppose that theadministered HCA is the tri-sodium salt of (−)-hydroxycitric acid. Insuch a case, since the tri-sodium salt has a molecular weight of 274g/mol and (−)-hydroxycitric acid is 208 g/mol, then administering 5,000mg of the tri-sodium salt would correspond to (5,000 divided by 274multiplied by 208) or 3,796 mg of (−)-hydroxycitric acid.

In some cases, the method further comprises determining an adjustedlevel of triglycerides or cortisol in the subject. Thus, a firstdetermining is performed, and then the administration is performed, andthen the second determining of the adjusted level is performed. Anysuitable length of time can elapse between each of these steps. Forinstance, 30 minutes to 300 minutes can elapse between the firstdetermining and the administration. For instance, 10 minutes to 600minutes can elapse between the administration and the seconddetermining, which is of the adjusted level. The first and subsequentadministrations typically, but not necessarily, involve administeringthe same HCA formulation.

In some cases, the method further comprises performing a secondadministration of a formulation comprising HCA in an amount based on thedifference between the initial level and the adjusted level. Forexample, if triglycerides or cortisol did not measurably change, then alarger amount of HCA can be administered. However, if blood oxygensaturation decreased measurably, then the second administration can beof a smaller maintenance dose to keep the triglycerides or cortisol ator near the desired range. This cycle of determining the level oftriglycerides or cortisol and administering HCA can be repeated anysuitable number of times, with any suitable length of time elapsingbetween each step. A medical professional can use their professionaljudgement to determine such factors.

As described above, the HCA can be (−)-hydroxycitric acid, a saltthereof, or a derivative thereof. Suitable salts include sodium,potassium, calcium, magnesium, and potassium-magnesium. Suitablederivates include a lactone, an amide, and an ester. As such, in somecases, the HCA is selected from the group consisting of(−)-hydroxycitric acid, a lactone of (−)-hydroxycitric acid, a sodiumsalt of (−)-hydroxycitric acid, a potassium salt of (−)-hydroxycitricacid, a calcium salt of (−)-hydroxycitric acid, a magnesium salt of(−)-hydroxycitric acid, a potassium-magnesium salt of (−)-hydroxycitricacid, an amide derivative of (−)-hydroxycitric acid, and an esterderivative of (−)-hydroxycitric acid.

In some case, the HCA is a potassium-magnesium salt of (−)-hydroxycitricacid.

As described above, this method can be used to decrease triglycerides orcortisol. As such, it is useful for treating subjects with unhealthilyhigh triglycerides or cortisol. Due to variations between individuals,what is unhealthy depends upon numerous factors, and as such no singlenumerical value necessarily separates a healthy triglycerides orcortisol level from an unhealthy blood oxygen saturation level. In somecases, prior to the administration, a medical professional determinedthat the triglycerides or cortisol of the patient is unhealthily high.The medical profession can be, for example, a doctor, nurse, orparamedic.

In some cases, the determining is of triglycerides. For example, theinitial level of triglycerides can be determined by a medicalprofessional to be too high. Sometimes the initial level oftriglycerides is 150 mg/dL or more, such as 250 mg/dL or more, 400 mg/dLor more, or 500 mg/dL or more.

In some cases, the determining is of cortisol. In some cases, theinitial level of cortisol was determined by a medical professional to beunhealthily high. In some cases, the initial level of cortisol was 25μg/dL or more.

In some cases, the subject has been diagnosed by a medical professionalwith one or more conditions selected from the group consisting of:dementia, insulin resistance, reactive hyperglycemia, diabetes, elevatedblood sugar levels, mental stress, and physical stress.

The HCA can be administered in any suitable fashion. For instance, theHCA can be administered orally, e.g. as a solid, as an aqueous solution,in a capsule, or in a pill. Alternatively, the HCA can be administeredintravenously.

In some cases, the amount of HCA administered is sufficient to reducetriglycerides by 5% or more within 6 hours, such as by 10% or more, 20%or more, 30% or more, or 50% or more. In some cases the reduction occurswithin 2 hours, such by 5% or more, such as by 10% or more, 20% or more,30% or more, or 50% or more.

In some cases, the amount of HCA administered is sufficient to reducecortisol by 5% or more within 6 hours, such as by 10% or more, 20% ormore, 30% or more, or 50% or more. In some cases the reduction occurswithin 2 hours, such by 5% or more, such as by 10% or more, 20% or more,30% or more, or 50% or more.

In some cases, the method further includes administering triglyceridesor coconut oil. In some cases, the method further includes administeringa supplement promoting hepatic ketogenesis, e.g. carnitine oralpha-glyceryl phosphoryl choline.

Kit Relating to Triglycerides

Provided is a kit including HCA and instructions directing a subject toingest the HCA if the subject is determined to have an unhealthily hightriglyceride level.

If appropriate, each of the aspects discussed above regarding the methodof reducing triglycerides can also be applied to the kit described inthis section.

In some cases, the instructions direct the subject to ingest HCAcorresponding to 500 mg to 10,000 mg of (−)-hydroxycitric acid, such as1,500 mg to 5,000 mg. In some cases, according to the instructions, theunhealthily high triglyceride level is 150 mg/dL or more, such as 250mg/dL or more, 400 mg/dL or more, or 500 mg/dL or more. HCA can beselected from the group consisting of (−)-hydroxycitric acid, a lactoneof (−)-hydroxycitric acid, a sodium salt of (−)-hydroxycitric acid, apotassium salt of (−)-hydroxycitric acid, a calcium salt of(−)-hydroxycitric acid, a magnesium salt of (−)-hydroxycitric acid, apotassium-magnesium salt of (−)-hydroxycitric acid, an amide derivativeof (−)-hydroxycitric acid, and an ester derivative of (−)-hydroxycitricacid. Sometimes the HCA is a potassium-magnesium salt of(−)-hydroxycitric acid.

In some cases, the kit further includes a triglyceride measurementdevice, wherein the instructions direct the subject to determine thetriglyceride level with the triglyceride measurement device. In somecases, the triglyceride measurement device also measures cholesterollevels.

The instructions can be provided in any suitable manner, e.g. as a labelattached to a container holding the HCA, or on a piece of paper includedin a packaging along with a container holding the HCA. The HCA can be asolid, in an aqueous solution, in a capsule, or in a pill. In somecases, the HCA is in the form of an aqueous solution.

Also provided is method including packaging a formulation includingpackaging into a container HCA and instructions directing a subject toingest the HCA if the subject is determined to have unhealthily hightriglycerides. This method corresponds to the kit described in thissection, and can include each of the aspects described above relating tothe kit.

In some cases, the kit further includes triglycerides or coconut oil. Insome cases, the kit further includes administering a supplementpromoting hepatic ketogenesis, e.g. carnitine or alpha-glycerylphosphoryl choline.

Method of Treating a Sleep Problem

It has been recognized that cortisol levels in an animal typicallyfollow a diurnal cycle, i.e. they increase and decrease according to anendogenous, entrainable oscillation of about 24 hours. This cycle isalso sometimes called a circadian rhythm or a diurnal rhythm.

Since administration of HCA has been shown herein to influence cortisollevels, the inventors also provide a method of treating a subject for asleep problem. In particular, provided is a method of treating asubject, including administering to the subject a therapeuticallyeffective amount of a formulation including HCA, wherein a medicalprofessional has determined that the subject has a sleep problem,thereby reducing the sleep problem. In some cases, this reductioninvolves a decrease severity of the problem, the frequency of theproblem, or both. In some cases, this reduction involves a completeclearance of the problem.

In some cases, the problem is jet lag. Jet lag is a phenomenon wherein asubject quickly moves from one location on Earth to another location onEarth, e.g. via a jet airplane, and therefore the subject's innate 24hour cycle of hormones and other internal processes is out of sync withthe sun cycle at the destination. Administering HCA can help thesubject's internal cortisol cycle to become more quickly synced with the24 hour cycle at the destination. For example, typical cortisol levelsare 5 μg/dL to 25 μg/dL at 9 am, and 2.9 μg/dL to 13 μg/dL at midnight.Thus, cortisol levels are somewhat lower at midnight than at 9 am. Thus,in some cases, the administration of HCA can be in the evening (of thedestination's time zone), thereby decreasing cortisol levels in the samemanner that cortisol levels are decreased naturally. The administrationof HCA can be before, after, or both relative to the transit betweentime zones.

In some cases, the problem is insomnia. HCA can be administered at anysuitable time of day.

If appropriate, each of the aspects discussed above regarding the methodof reducing cortisol can also be applied to the kit described in thissection.

In some cases, the administered HCA corresponding to 500 mg to 10,000 mgof (−)-hydroxycitric acid, such as 1,500 mg to 5,000 mg. HCA can beselected from the group consisting of (−)-hydroxycitric acid, a lactoneof (−)-hydroxycitric acid, a sodium salt of (−)-hydroxycitric acid, apotassium salt of (−)-hydroxycitric acid, a calcium salt of(−)-hydroxycitric acid, a magnesium salt of (−)-hydroxycitric acid, apotassium-magnesium salt of (−)-hydroxycitric acid, an amide derivativeof (−)-hydroxycitric acid, and an ester derivative of (−)-hydroxycitricacid. Sometimes the HCA is a potassium-magnesium salt of(−)-hydroxycitric acid.

In some cases, the method further includes administering triglyceridesor coconut oil. In some cases, the method further includes administeringa supplement promoting hepatic ketogenesis, e.g. carnitine oralpha-glyceryl phosphoryl choline.

Kit Relating to Cortisol and Sleep

Provided is a kit including HCA and instructions directing a subject toingest the HCA if the subject has or is expected to have a sleepproblem.

If appropriate, each of the aspects discussed above regarding the methodof reducing cortisol can also be applied to the kit described in thissection.

In some cases, the sleep problem is jet lag. In other cases, the sleepproblem is insomnia.

In some cases, the instructions direct the subject to ingest HCAcorresponding to 500 mg to 10,000 mg of (−)-hydroxycitric acid, such as1,500 mg to 5,000 mg. HCA can be selected from the group consisting of(−)-hydroxycitric acid, a lactone of (−)-hydroxycitric acid, a sodiumsalt of (−)-hydroxycitric acid, a potassium salt of (−)-hydroxycitricacid, a calcium salt of (−)-hydroxycitric acid, a magnesium salt of(−)-hydroxycitric acid, a potassium-magnesium salt of (−)-hydroxycitricacid, an amide derivative of (−)-hydroxycitric acid, and an esterderivative of (−)-hydroxycitric acid. Sometimes the HCA is apotassium-magnesium salt of (−)-hydroxycitric acid.

The instructions can be provided in any suitable manner, e.g. as a labelattached to a container holding the HCA, or on a piece of paper includedin a packaging along with a container holding the HCA. The HCA can be asolid, in an aqueous solution, in a capsule, or in a pill. In somecases, the HCA is in the form of an aqueous solution.

Also provided is method including packaging a formulation includingpackaging into a container HCA and instructions directing a subject toingest the HCA if the subject has or is expected to have a sleepproblem. This method corresponds to the kit described in this section,and can include each of the aspects described above relating to the kit.

In some cases, the kit further includes triglycerides or coconut oil. Insome cases, the kit further includes administering a supplementpromoting hepatic ketogenesis, e.g. carnitine or alpha-glycerylphosphoryl choline.

Improving a Subject's Performance on a Task

Also provided are methods, kits, and uses of HCA for improving asubject's performance on a task. For instance, provided is a method ofimproving a subject's performance on a task by administering HCA to thesubject and performing the tasks. Exemplary tasks include games, mentaltasks, and athletic tasks.

For instance, in some cases the tasks is a game, such as a video game.Video games involve a user providing input to an electronic device thatcreates visual feedback to the user. For instance, the user input can beprovided by a mouse, keyboard, joystick, or motion sensing device. Thevisual feedback can be displayed on a device such as a television orcomputer monitor. The video game can be performed by the user, in somecases, using a mouse and a keyboard. In some cases the video gameinvolves competition between different people who are each providinginput to the game. In some cases the video games are played as part of acompetitive league, which are sometimes referred to as “E-sports” or“electronic sports” leagues. Exemplary video games that are sometimesplayed as part of E-sports leagues include first-person shooter games(e.g. Counter-Strike), real-time strategy games (e.g. StarCraft), andmultiplayer online battle arena games (e.g. League of Legends).Sometimes success at the game depends on reaction time of the subjectand the game involves multiple players acting simultaneously, incontrast to turn-based games wherein players perform actions atdifferent times (i.e. different turns). The present HCA compositionsdescribed herein can in some cases increase performance on such games,such as by increasing blood oxygenation or energy utilization.

In some cases, the task an “activity of daily living”. For instance, thetask can be walking, standing, or holding an object in the hand of thesubject. Additional activities of daily living include using a bathroomby oneself, preparing a meal, and washing dishes. For instance, somesubjects can have a movement disorder, such as Parkinson's disease oressential tremor, that can reduce the ability to perform activities ofdaily living. For example, the subject can have reduced hand-eyecoordination, making it difficult to clean items, wash oneself, moveobjects, or feed oneself.

In some cases, the task is a mental task. For instance, the task can beremembering, such as remembering to perform a daily task, remembering totake medications, or remembering the identities of friends or family. Insome cases, the mental task is an executive function, such as attentioncontrol, cognitive inhibition, inhibition control, working memory,cognitive flexibility, planning, reasoning, and problem solving. In somecases the task is short-term memory or long-term memory. In someembodiments the subject has been diagnosed with a mental disorder, suchas a memory disorder. In some cases the subject has dementia, such asAlzheimer's disease. Another mental tasks include academic tasks, suchas academic studying, completing an academic assignment, or taking anacademic test. The present HCA compositions described herein can in somecases increase performance on such tasks, such as by increasing bloodoxygenation or energy utilization.

In addition, the task can be an athletic tasks, such as running,walking, strength training, weight lifting, or swimming. In some casesthe athletic task is aerobic endurance, and administration of the HCAimproves aerobic endurance. In some cases the tasks can also beanaerobic athletic ability, such as short periods of weight lifting. Insome cases, the tasks is a physical game. Exemplary physical gamesinclude association football, baseball, basketball, cricket, ice hockey,kick boxing, table tennis, American football, and Gaelic football. Thepresent HCA compositions described herein can in some cases increaseperformance on such tasks, such as by increasing blood oxygenation orenergy utilization.

Additional Aspects

Also provided are compositions for use in treating a subject for any ofthe situations described herein. Also provided are the use of HCA in themanufacture of a medicament for the treatment of any of the situationsdescribed herein.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Example 1—Creating an HCA Formulation

An aqueous formulation was created that included purified water, apotassium-magnesium salt of (−)-hydroxycitric acid, glycerol, andlimonene according to the procedure of U.S. Pat. No. 10,376,483. First,1.25 ml of glycerol was combined with 3.75 ml of purified water,yielding 5 ml of liquid. Next, 1,500 mg of a potassium-magnesium salt of(−)-hydroxycitric acid was added to the water-glycerol mixture. Sincethe HCA salt was approximately 69.7% hydroxycitrate, this corresponds toabout 1,047 mg of (−)-hydroxycitric acid. Lastly, 20 mg of limonene wasadded and the liquid was stirred until all items are dissolved andstable. Limonene is a monoterpene that can be used to modify theviscosity of the liquid, e.g. to adjust for nozzle size and fillingspeed if the aqueous formulation is put into a capsule.

Example 2—Effect of the Example 1 Formulation on Blood Hemoglobin andOxygen Saturation

Subjects 1-4 were orally administered the formulation of Example 1. TheSubjects were given either one or two administrations of 8.33 ml of theaqueous formulation of Example 1 on an empty stomach, i.e. wherein witheach 8.33 ml the subject received 2,500 mg of the potassium-magnesium(−)-hydroxycitric acid salt, corresponding to 1745 mg of(−)-hydroxycitric acid.

fNIRS testing (functional Near Infrared Spectroscopy) was used tomeasure blood hemoglobin and oxygen saturation. fNIRS can be used todetermine real-time peripheral and cerebral hemodynamic responses. Forexample, relative changes in HbR (deoxygen saturation), HbO (oxygensaturation), and HbT (total hemoglobin concentration), etc. can bedetermined via application of Modified Beer Lambert Law. HbR,Hb=deoxygen saturation (shown as the thinnest and bottom dashed line inFIG. 1) HbO, HbO2=oxygen saturation (shown as the medium-thickness andmiddle line in FIG. 1) HbT=total hemoglobin concentration (shown as thedarkest, thickest and top line in FIG. 1). On the graphs, time is inseconds.

FIG. 1 shows the results of administration to Subject 1, a middle-agedmale. The section before the first vertical line is the reference orbaseline period. This line also marks the dosing point. The sectionafter the second vertical line indicates a rather dramatic change inblood hemoglobin and oxygen levels that began 12-15 minutes followingdosing.

FIG. 2 shows the results of administration to Subject 2, a late-50smale. The vertical lines correspond to a first administration of 8.33 mland a second administration of another 8.33 ml. Blood hemoglobin andoxygen saturation levels increased.

FIG. 3 shows the results of the administration to Subject 3, a maleapproximately 50 years old. The first administration of 8.33 ml is atthe start of the graph and a second administration of another 8.33 ml isat the vertical line. Blood hemoglobin and oxygen saturation levelsincreased.

FIG. 4 shows the results of the administration to Subject 4, a female ofapproximately 30 years. Blood hemoglobin and oxygen saturation levelsincreased.

Example 3—Effect of the Example 1 Formulation on Levels of Biomolecules,Such as Triglycerides, Cortisol, and Ketones

Subject 5 was a late-60s male, weighing approximately 285 pounds andwith a normal fasting blood sugar level of 115-120. First, blood wasdrawn from Subject 5 and levels of various biomolecules were measured.Next, Subject 5 was administered 16.66 ml of the Example 1 formulationon an empty stomach, i.e. wherein with each 16.66 ml the subjectreceived 5,000 mg of the potassium-magnesium (−)-hydroxycitric acidsalt, corresponding to 3490 mg of (−)-hydroxycitric acid. 90 minutesafter the administration, blood was drawn from Subject 5 and levels ofthe various biomolecules were remeasured. The results are shown in thetable below.

Subject 5 Before administration 90 mins after administration (fasting)Percentage Normal Biomarker Result Result Change Change Range UnitsCortisol (9 am) 336 281 −55 −19.57 166- nmol/L 507 HDL 1.72 1.78 0.063.37 1.1< mmol/L HDL % of Total 31.7 33.5 1.73 5.17 20< % CholesterolHbA1c 34.4 36.3 1.99 5.48 20-42 mmol/mol LDL 2.98 3.11 0.13 4.18 0-3mmol/L Thyroid 1.56 1.26 −0.3 −23.81 0.27- Stimulating 4.2 mIU/L Hormone(TSH) Total Cholesterol 5.42 5.32 −0.1 −1.88 0-5 mmol/L Triglycerides1.59 0.95 −0.64 −67.37 0-1.7 mmol/L Ketones 0.6 0.5

FSB Values:

U.S. value=UK/Canadian value times 18 (mmol/L×18=mg/dl).

U.K./Canadian value=U.S. value divided by 18 (mg/dl/18=mmol/L).

As can be seen from the table, triglycerides decreased from 1.59 to0.95, for a net change of minus 0.64 and a percentage change of minus67%. As also shown in the table, cortisol decreased from 336 to 281, fora net change of minus 55 and a percentage change of minus 20%.

Since triglycerides are metabolized into ketones, it was hypothesizedthat decreased triglyceride levels would coincide with an increase inketone levels. In contrast, however, ketone levels decreased from 0.6 to0.5 after administration of HCA. In essence, the ketone levels stayedthe same or experienced a minor decrease after HCA administration.Therefore, it was hypothesized that HCA administration not only producedmore ketones from triglycerides, but resulted in an even larger increasethe metabolisms of ketones by mitochondria to produce energy. Sincemitochondria normally metabolize glucose to generate energy, the glucosewas replaced with ketones. Furthermore, the fact that metabolizing someketones consumes less oxygen provides a possible explanation of whyother subjects (in Example 2) experienced increased blood oxygensaturation upon HCA administration.

As such, the overall hypothesized mechanism is shown in FIG. 5. Namely,administration of HCA increases the metabolism of triglycerides intoketones. In addition, mitochondria use more ketones and less glucose togenerate energy. Since metabolizing ketones can sometimes consume lessoxygen, blood oxygen saturation increases.

There was also a significant elevation of the subject's blood sugarlevels. It is hypothesized that this transient elevation is due toRandall's Cycle. Since the subject was significantly overweight, inmetabolizing the triglycerides quickly, it is possible that the HCA wasmobilizing too much energy to be disposed of immediately. In support ofthis explanation, it is noted that this subject had previously used HCAformulations with the result of keeping his otherwise elevated fastingblood glucose levels in the low- to mid-90s with consistent usage.

Subject 6 was administered 16.66 ml of the Example 1 formulation on anempty stomach, i.e. wherein with each 16.66 ml the subject received5,000 mg of the potassium-magnesium (−)-hydroxycitric acid salt,corresponding to 3490 mg of (−)-hydroxycitric acid. 90 minutes after theadministration, blood was drawn from Subject 6 and levels of the variousbiomolecules were remeasured. The results are shown in the table below.

Subject 6 Before administration 90 mins after administration (fasting)Percentage Normal Biomarker Result Result Change Change Range UnitsCortisol (9 am) 376 319 −57 −15.2% 166- nmol/L 507 HDL 1.66 1.72 0.063.61% 1.1< mmol/L HDL % of Total 33.7 33.4 −0.27 −0.80% 20< %Cholesterol HbA1c 34.6 35.3 0.71 2.05% 20-42 mmol/mol LDL 2.81 3.03 0.227.83% 0-3 mmol/L Thyroid 2.31 1.98 −0.33 −14.3% 0.27- Stimulating 4.2mIU/L Hormone (TSH) Total Cholesterol 4.93 5.15 0.22 4.46% 0-5 mmol/LTriglycerides 1.01 0.89 −0.12 −11.9% 0-1.7 mmol/L

As can be seen from the table, triglycerides decreased from 1.01 to0.89, for a net change of minus 0.12 and a percentage change of minus11.9%. As also shown in the table, cortisol decreased from 376 to 319,for a net change of minus 57 and a percentage change of minus 15%.

Example 4—Effect of the Example 1 Formulation on Sleep and Stress

Subject 7 was a 60 year-old male of approximately 6 feet tall andaverage body mass. He was a cancer survivor who had been treated foresophageal cancer with surgery, chemotherapy, and radiation. Afterovercoming the cancer, Subject 7 tried ingesting the Example 1formulations to see if it would help with stress and his disturbedsleep. He stated that he got a buzz in the temples within 15-20 minutes.He further reported tingling in his fingers and toes, which he said wassurprising since he had nerve damage in his extremities due to thechemotherapy. He stated that there was a quite noticeable change as aresult of ingesting the Example 1 formulation. He also found that theExample 1 formulation helped him sleep better and feel better generally.

Example 5—Effect of the Example 1 Formulation on Athletic Performanceand Jet Lag

Subject 8 was a medium-build male of approximately 50 years of age.Subject 8 was a distance runner. He consumed 15 ml at a time of theExample 1 formulation. He reported a rapid onset of mental clarity.Within 1-2 days of ingesting the Example 1 formulations, he found thathis athletic endurance and recovery improved dramatically to the pointthat he could run a 10,000 meter course in the morning and then doweight training late in the afternoon on the same day—something he couldnever do before. He also reported that he suffered little to no jet lagafter flying coast-to-coast, which is a regular trip for him.

Subject 9 was a large middle-aged male of approximately 50 years of ageand an extreme long-distance runner. He consumed 10-15 ml of the Example1 formulation at a time and reported that within the first week he hadmuch greater athletic endurance and better recovery.

Conclusion

HCA administration was found to result in decreased triglycerides,relatively stable or slightly lower levels of ketones, increasedglucose, increased oxygen saturation, increased blood hemoglobin, anddecreased cortisol. In some cases the increase in glucose is transientand only for a short time. As shown in FIG. 5, it is hypothesized thatHCA directly increases metabolism of triglycerides into ketones, butalso the metabolism of ketones by mitochondria such that overall ketonelevels stay relatively constant or slightly decrease. Since mitochondriause more ketones, they also metabolize less glucose, leading to anincrease in glucose levels. Since mitochondrial metabolism of ketonesrequires less oxygen that glucose metabolism, blood oxygen saturationincrease. It is hypothesized that cortisol decreases and bloodhemoglobin increases through separate and not yet elucidated mechanisms.

Example 6—Effect of HCA Administration on Parkinson's Disease

It is hypothesized that administration of HCA can be used to treatParkinson's disease. In particular, it has been reported that increasedketone production can reduce abnormal accumulation of alpha-synuclein inthe brain, wherein the alpha-synuclein is associated with Parkinson'sdisease (Sheila Marie Fleming, “Effect of Dietary Ketosis onAlpha-Synuclein Accumulation”, Michael J Fox Foundation for Parkinson'sResearch). In fact, ketogenic diets have been shown to reduceaccumulation of alpha-synuclein in the brain (Id.). Thus, since HCA canincrease ketone utilization, as described above, HCA administration ishypothesized to help treat Parkinson's disease through a mechanismsimilar to the ketogenic diet. An additional study stating that ketonescan influence Parkinson's disease is Norwitz et al, Frontiers inNutrition, 2019, doi:10.3389/fnut.2019.00063.

The preceding merely illustrates the principles of the invention. Itwill be appreciated that those skilled in the art will be able to devisevarious arrangements which, although not explicitly described or shownherein, embody the principles of the invention and are included withinits spirit and scope. Furthermore, all examples and conditional languagerecited herein are principally intended to aid the reader inunderstanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

1-35. (canceled)
 36. A method of improving a subject's performance on atask, comprising: administering HCA to the subject, wherein HCA is(−)-hydroxycitric acid, a salt thereof, or a derivative thereof; andperforming the task.
 37. The method of claim 36, wherein the task is agame.
 38. The method of claim 37, wherein the game is a video game.39-41. (canceled)
 42. The method of claim 36, wherein the task is anactivity of daily living.
 43. The method of claim 42, wherein thesubject has been diagnosed with a movement disorder.
 44. The method ofclaim 43, wherein the movement disorder is Parkinson's disease.
 45. Themethod of claim 36, wherein the task is a mental task.
 46. The method ofclaim 45, wherein the mental task is remembering.
 47. The method ofclaim 46, wherein the subject has been diagnosed with a memory disorder.48. The method of claim 47, wherein the subject has been diagnosed withdementia.
 49. The method of claim 48, wherein the subject has beendiagnosed with Alzheimer's disease.
 50. The method of claim 45, whereinthe mental task is an academic task.
 51. The method of claim 36, whereinthe task is an athletic task.
 52. The method of claim 51, wherein theathletic task is aerobic endurance.
 53. The method of claim 37, whereinthe game is a physical game.
 54. The method of any one of claims 36-53,wherein administered HCA corresponds to 500 mg to 10,000 mg of(−)-hydroxycitric acid. 55-57. (canceled)
 58. The method of any one ofclaims 36-54, further comprising hypothesizing or determining that thesubject's performance on the task would improve if mitochondria of thesubject metabolized more ketones, wherein the hypothesizing ordetermining is performed before the administration.
 59. A kitcomprising: HCA, and instructions directing a subject to ingest the HCAif the subject desires increased performance on a task, wherein HCA is(−)-hydroxycitric acid, a salt thereof, or a derivative thereof.
 60. Thekit of claim 59, wherein the task is selected from the group consistingof: a game, an activity of daily living, a mental task, an academictask, and an athletic task.
 61. The kit of claim 59 or 60, wherein theinstructions direct the subject to ingest a dose of HCA corresponds to500 mg to 10,000 mg of (−)-hydroxycitric acid.
 62. (canceled)